Driver Mutations in Leukemia Promote Disease Pathogenesis through a Combination of Cell-Autonomous and Niche Modulation

Baskar Ramdas, Raghuveer Singh Mali, Lakshmi Reddy Palam, Ruchi Pandey, Zhigang Cai, Santhosh Kumar Pasupuleti, Sarah S. Burns, Reuben Kapur

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Studies of patients with acute myeloid leukemia (AML) have led to the identification of mutations that affect different cellular pathways. Some of these have been classified as preleukemic, and a stepwise evolution program whereby cells acquire additional mutations has been proposed in the development of AML. How the timing of acquisition of these mutations and their impact on transformation and the bone marrow (BM) microenvironment occurs has only recently begun to be investigated. We show that constitutive and early loss of the epigenetic regulator, TET2, when combined with constitutive activation of FLT3, results in transformation of chronic myelomonocytic leukemia-like or myeloproliferative neoplasm-like phenotype to AML, which is more pronounced in double-mutant mice relative to mice carrying mutations in single genes. Furthermore, we show that in preleukemic and leukemic mice there are alterations in the BM niche and secreted cytokines, which creates a permissive environment for the growth of mutation-bearing cells relative to normal cells.

Original languageEnglish (US)
Pages (from-to)95-109
Number of pages15
JournalStem Cell Reports
Volume15
Issue number1
DOIs
StatePublished - Jul 14 2020

Keywords

  • AML
  • CMML
  • Flt3ITD/ITD
  • MPN
  • TET2
  • bone marrow microenvironment
  • cytokines

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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